Understanding the parameters guiding the best practice for treating B‐cell‐depleted patients with COVID‐19 convalescent plasma therapy

The commentary by Focosi et al. ¹ highlights two key aspects of the patient‐blood management for coronavirus disease 2019 (COVID‐19) convalescent plasma (CCP) therapy in seronegative patients who are pre‐exposed to B‐cell‐depleting agents. The first one relates to the qualitative composition of CCP used for patient treatment. The efficacy of CCP is strongly affected by the titres of neutralising antibodies (nAb) present at the time of donation. ² , ³ Moreover, there is growing evidence that the nAb activity of plasma units collected from unvaccinated donors infected during the former COVID‐19 waves is reduced against novel variants such as Omicron. ⁴ Hence, the efficacy of collected plasma is likely evolving alongside the exposure of potential donors to successive variant outbreaks and vaccination campaigns against severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2).

At the beginning of the pandemic, CCP was used as a front‐line treatment; however, its wide heterogeneity in nAb titres made it difficult to recruit suitable donors of high neutralising titres, as defined by the United States Food and drug Administration (FDA). In contrast, nAb induced after two doses of mRNA vaccination have generally higher and more homogenous titres, which further remain effective against Omicron following a booster dose. ⁵ From March to July 2021, we treated 19 immunosuppressed patients with plasma collected from COVID‐naive two‐dose mRNA‐vaccinated donors, under a compassionate use protocol, according to the Swiss regulation rules. ⁶ No relevant difference was observed between patients receiving CCP (n = 17) versus vaccinated plasma (VP, n = 19), indicating that VP therapy is safe and effective in patients with B‐cell lymphopenia. In the meantime, CCP donors are increasingly getting vaccinated, and three‐dose VP donors are being boosted by a breakthrough infection (defined as ‘hybrid plasma’, Vax‐CCP or CP/VP). Their plasmas contain higher nAb titres and broader antibody specificity than CCP, ⁴ , ⁷ , ⁸ as shown by the increase in anti‐spike immunoglobulin G titres between 2021 and 2022 (Figure 1A). Thus, Vax‐CCP is emerging as the most convenient available source of polyclonal antibody plasma, given the failure of many monoclonal antibody therapies, due to the Omicron immune escape variants. ⁹

FIGURE 1.

SARS‐CoV‐2 viral load response follow‐up in B‐cell‐depleted patients (n = 11) treated with plasma therapy (from December 2021 through September 2022). All patients had received anti‐CD20 therapy and, except of one patient, were hospitalised for moderate to severe COVID‐19. A favourable clinical outcome was observed in 10 out the 11 plasma‐treated patients. (A) Anti‐spike (anti‐S) protein IgG titres were collected from COVID‐19‐experienced only plasma donors (2020, October 2020–February 2021) or COVID‐19‐experienced vaccine‐boosted (VaxCCP or CP/VP) plasma donors (2021, June–August 2021; 2022, February–September 2022). (B) Comparison of anti‐S IgG antibody titres in each patient before and after 1 × CP/VP or 2 × CP/VP treatment, using an in‐house developed Luminex assay. ¹¹ The maximum reached value is depicted. (C) The PANGO lineage is indicated for each patient. (D) SARS‐CoV‐2 RNA detection ¹² in nasopharyngeal (NP) swabs (copies/ml) before (Day –5 to Day 0) treatment and over‐time kinetics after treatment with 1 × CP/VP (1×) or 2 × CP/VP (2×). The p value is by Mann–Whitney test. (E) Time‐to‐negativity of the NP swabs in patients treated with 1 × CP/VP (1×) or 2 × CP/VP (2×). CCP, COVID‐19 convalescent plasma; COVID‐19, coronavirus disease 2019; IgG, immunoglobulin G; n.s., not significant; PANGO, Phylogenetic Assignment of Named Global Outbreak; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2; VP, vaccinated plasma.

The second key aspect commented upon by Focosi et al ¹ concerns the best practice for treating immunocompromised seronegative patients with COVID‐19 with plasma therapy. It still remains to be defined which therapeutic plasma protocol is optimal to achieve a rapid and complete viral response. ¹⁰ In this regard, Focosi et al ¹ propose to start with a loading Vax‐CCP dose of 600 ml followed by weekly 600‐ml dose transfusion, allowing for a faster viral clearance in patients than those receiving a single‐dose unit. In our centre, we use an initial 400‐ml dose of Vax‐CCP issued from two vaccinated and recently‐infected donors having recovered from a contemporary viral strain. In case of insufficient clinical and/or viral load response, we treat again with the same plasma dose but from other convalescent vaccine‐boosted individuals. Using this strategy, we recently followed the SARS‐CoV‐2 viral load response in 11 B‐cell‐depleted antibody‐negative patients with a documented onco‐haematological (seven patients) or autoimmune disorder (four patients), after plasma therapy. Patients were classified according to whether they had Vax‐CCP treatment once or twice (Figure 1B) and presented various Phylogenetic Assignment of Named Global Outbreak (PANGO) lineages, depending on the predominant circulating strain(s) at the time of diagnosis (Figure 1C). Our data indicate that seven out nine patients were able to clear the virus within the same time‐range (<35 days, Figure 1D,E) as reported for patients with endogenous anti‐SARS‐CoV‐2 responses, ⁶ among them two had received two serial transfusions. Hence, our tailored approach is consistent with the relative low number of refractory cases (six of 36) previously observed ⁶ and enables sparing Vax‐CCP resources of high anti‐SARS‐CoV‐2 titres, which heavily rely on the continuous collection of donor plasma.

Understanding which parameter(s) may be predictive of complete viral clearance would likely help adjusting Vax‐CCP treatment. As such, the question of whether basal viral load is typically higher in B‐cell‐depleted patients than in B‐cell‐undepleted ones and thus represents a red‐flag could alas not be addressed in the dataset initially reported, ⁶ as both cohorts differed substantially in terms of the underlying viral variant (pre‐alpha vs. alpha predominance respectively). Still, we recently observed that patients transfused twice with Vax‐CCP had higher levels of initial SARS‐CoV‐2 viral loads than those receiving only one‐time plasma (Figure 1D). These observations suggest that viral loads before Vax‐CCP treatment may potentially define those seronegative patients more at risk of delayed clinical recovery and/or viral clearance, and who would require additional transfusions. Importantly, randomised controlled trials, like the recently reopened Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community‐Acquired Pneumonia (REMAP‐CAP) trial, specifically focusing on immunocompromised patients treated with Vax‐CCP, should further help addressing such important points, paving future guidelines for the use of therapeutic plasma.

AUTHOR CONTRIBUTIONS

Nathalie Rufer wrote the first draft; David Gachoud, Claire Bertelli and Nathalie Rufer revised the manuscript.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

PATIENT CONSENT STATEMENT

Each patient provided informed consent for plasma transfusion and data collection.

DATA AVAILABILITY STATEMENT

The datasets that support the findings of this study are available from the corresponding author upon reasonable request.